Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways.
Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways.
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内皮细胞GATA6缺失通过Cmpk2-Nlrp3通路减少单核细胞募集和促炎巨噬细胞的形成，从而减轻动脉粥样硬化。
DOI：
10.1016/j.redox.2023.102775
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发表时间：
2023-08
期刊：
影响因子：
11.4
通讯作者：
Zhuang, Tao
中科院分区：
文献类型：
--
作者：
Wu, Wenrun;Bao, Wenzhen;Chen, Xiaoli;Lu, Yushi;Fang, Ji;Liu, Jiwen;Peng, Sheng;Pi, Jingjiang;Tomlinson, Brian;Chan, Paul;Zhang, Qi;Zhang, Lin;Liu, Zhongmin;Liu, Jie;Zhang, Yuzhen;Zhuang, Tao
关键词：
Endothelial dysfunction results in chronic vascular inflammation, which is critical for the development of atherosclerotic diseases. Transcription factor Gata6 has been reported to regulate vascular endothelial cell activation and inflammation in vitro. Here, we aimed to explore the roles and mechanisms of endothelial Gata6 in atherogenesis. Endothelial cell (EC) specific Gata6 deletion was generated in the ApoeKO hyperlipidemic atherosclerosis mouse model. Atherosclerotic lesion formation, endothelial inflammatory signaling, and endothelial-macrophage interaction were examined in vivo and in vitro by using cellular and molecular biological approaches. EC-GATA6 deletion mice exhibited a significant decrease in monocyte infiltration and atherosclerotic lesion compared to littermate control mice. Cytosine monophosphate kinase 2 (Cmpk2) was identified as a direct target gene of GATA6 and EC-GATA6 deletion decreased monocyte adherence, migration and pro-inflammatory macrophage foam cell formation through regulation of the CMPK2-Nlrp3 pathway. Endothelial target delivery of Cmpk2-shRNA by intercellular adhesion molecule 2 (Icam-2) promoter-driven AAV9 carrying the shRNA reversed the Gata6 upregulation mediated elevated Cmpk2 expression and further Nlrp3 activation and thus attenuated atherosclerosis. In addition, C–C motif chemokine ligand 5 (Ccl5) was also identified as a direct target gene of Gata6 to regulate monocyte adherence and migration influencing atherogenesis. This study provides direct in vivo evidence of EC-GATA6 involvement in the regulation of Cmpk2-Nlrp3, as well as Ccl5, on monocyte adherence and migration in atherosclerosis development and advances our understanding of the in vivo mechanisms of atherosclerotic lesion development, and meanwhile provides opportunities for future therapeutic interventions. Elevated Gata6 expression in ECs of atherosclerotic lesions, and EC-Gata6 regulates the development of atherosclerosis. EC-Gata6 regulates Cmpk2-Nlrp3 pathways resulting in monocyte recruitment and proinflammatory macrophage formation. Icam-2 promoter driven AAV9 endothelial target delivery of Cmpk2-shRNA suppresses atherosclerotic lesion formation.
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影响因子：
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作者：
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通讯作者：
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DOI：
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